Transcript The Pharmacology of Obesity - Endocrinology

The Pharmacology of
Obesity
Thomas Repas D.O.
Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, Wisconsin
Member, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program
Member, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WI
Member, Diabetes Steering Committee, Network Health Plan, Appleton, WI
Website: www.endocrinology-online.com
Overview
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Epidemic of obesity
Why treat obesity?
Pathophysiology of obesity
Pharmacology of obesity
– Pharmacology of drugs currently approved
for treatment of obesity
– Pharmacology of investigational agents
• Conclusion
Topics that I will not cover today……
• Dietary and nutritional recommendations
• Physical activity and other lifestyle
changes
• Surgical options for weight loss
The Epidemic of Obesity
Obesity in the U.S.
• More than 97 million
adults in US are
overweight or obese
(BMI >30)
– 19.9% of men
– 24.9% for women
Obesity Trends* Among U.S. Adults
BRFSS, 1985
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16,
2001;286:10.
Obesity Trends* Among U.S. Adults
BRFSS, 2001
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16,
2001;286:10.
Why Treat Obesity?
• Contributes to approximately 300,000 deaths a year,
making it 2nd only to smoking as a cause of death
• Contributes or causes to many other health problems
including:
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Type 2 Diabetes Mellitus
Coronary Artery Disease
Degenerative Joint Disease
Certain Types of Cancer
Nonalcoholic Steatohepatitis
Obesity Effects on Blood Pressure and Cholesterol
Costs of Obesity
• Costs the US health-care system more than $99 billion
each year
• Consumers also spend over $33 billion annually on weightreduction products and services
• Annual health-care costs for patients with BMIs of 20 to
24.9 were 20% lower than costs for patients with BMIs from
30 to 34.9 and almost 33% lower than for patients who had
BMIs of 35 or more.
Pathophysiology of Obesity
Pharmacology of Obesity
Potential Strategies for Anti-Obesity
Drug Action
• Reducing food intake. Either amplify effects of signals/factors that
inhibit food intake or block signals/factors that augment food intake
• Blocking nutrient absorption (especially fat or carbohydrates) in the
intestine.
• Increasing thermogenesis. Either increase metabolism and dissipate
food energy as heat or increase energy expenditure through the
enhancement of physical activity.
• Modulating fat metabolism/storage. Regulate fat
synthesis/breakdown by making appropriate adjustments to food intake or
energy expenditure.
• Modulating the central regulation of body weight. Either alter
the internal set point or modulate the signals presented regarding fat stores.
Currently Available Agents Indicated
for Treatment of Obesity
Generic/Brand Name
Usual Dose
Mechanism of Action
Side Effects
•Orlistat/Xenical
120 mg with each
meal
GI symptoms (oily
Peripheral: Blocks
absorption of about spotting, flatus with
discharge, fecal urgency,
30% of consumed fat oily stools, incontinence)
•Sibutramine/Meridia
5-15 mg/d
Central: Inhibits
synaptic reuptake of
norepinephrine and
serotonin
Dry mouth,
constipation,
headache, insomnia,
increased blood
pressure, tachycardia
•Phentermine/
Adipex, Fastin,
Ionamin and others
15-37.5 mg per
day as a single or
split dose
Central: Stimulates
release of
norepinephrine
CNS stimulation,
tachycardia, dry
mouth, insomnia,
palpitations
Agents sometimes used for Treatment of
Obesity NOT Indicated or FDA approved
Generic/Brand Name
Usual Dose
Mechanism of Action
Side Effects
•ephedrine+/-caffeine
"Elsinore"pill
Varies: usually
75-150 mg
ephedrine and
100-150 mg
caffeine
Central: Stimulates
CNS stimulation,
adrenergic receptors tachycardia, dry
mouth, insomnia,
palpitations
•Bupropion/Wellbutrin
100-300 mg/d
Central: Inhibits
reuptake of
dopamine
norepinephrine and
serotonin
CNS stimulation,
dry mouth,
headache, GI
effects
CNS: paresthesia,
•Topiramate/Topamax
96-192 mg/d
Uncertain: Central ? fatigue, dizziness,
memory difficulty,
concentration
difficulty, and
depression
INDICATIONS FOR USE OF OBESITY DRUGS
•A combined intervention of behavior therapy, dietary
changes and increased physical activity should be
maintained for at least 6 months before considering
pharmacotherapy.
NHLBI Obesity Education Initiative, Expert Panel on the Identification, Evaluation, and Treatment of
Overweight and Obesity in Adults
INDICATIONS FOR USE OF OBESITY DRUGS
• BMI of 30 kg/m² or more or a BMI of 27 kg/m² or
more with comorbid condition
• Understand that drug therapy is adjunctive to
lifestyle intervention
• Have realistic expectations about weight loss goals
and outcomes
• Demonstrate readiness for change
• Are unable to lose/maintain weight with lifestyle
change alone
• Comply with medication use
• Have no medical or psychiatric contraindications
ADDITIONAL CONSIDERATIONS WHEN USING
ANTI-OBESITY DRUGS
•Weight loss drugs should never be used without continued
concomitant lifestyle modifications and as part of a
comprehensive weight loss program.
•Continual assessment of drug therapy for efficacy and safety is
necessary.
•If the drug is efficacious in helping the patient to lose and/or
maintain weight loss and there are no serious adverse effects, it
can be continued.
•If not, it should be discontinued.
NHLBI Obesity Education Initiative, Expert Panel on the Identification, Evaluation, and Treatment of
Overweight and Obesity in Adults
CONTRAINDICATIONS OR CAUTIONS TO THE
USE OF OBESITY DRUGS
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Pregnancy or lactation
Unstable cardiac disease
Uncontrolled hypertension (SBP >180, DBP > 110 mmHg)
Unstable severe systemic illness
Unstable psychiatric disorder or history of anorexia
Other drug therapy, if incompatible (eg MAO inhibitors, migraine
drugs, adrenergic agents, arrhythmic potential)
• Closed angle glaucoma (caution)
• General anesthesia
NHLBI Obesity Education Initiative, Expert Panel on the Identification, Evaluation, and Treatment of
Overweight and Obesity in Adults
Pharmacology of Drugs
Currently Approved for
Treatment of Obesity
Sibutramine (Meridia)
• Appetite suppressant that works by blocking reuptake of
serotonin and norepinephrine.
• Some experts have postulated that this agent may be the
most effective in helping maintain weight loss.
• Maintaining weight loss has long been the major downfall
to most diet programs.
• Until recently, the longest clinical trials with this agent
have lasted 1 year.
•Meridia Video
Sibutramine (Meridia) Indications
Among obese patients who should undergo drug therapy,
sibutramine works best for those who:
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Experience difficulty controlling food intake
Do not feel full
Think about food a lot
Do not have increased cardiovascular disease risk or multiple
risk factors
• Are younger
Sibutramine is taken once daily with or without food.
Sibutramine (Meridia) Contraindications
The use of sibutramine is contraindicated in patients:
• Taking concomitant monoamine oxidase inhibitor
(MAOI) therapy
• With anorexia nervosa
• Using any other centrally-acting appetite
suppressant
• With hypersensitivity to ingredients of sibutramine
Sibutramine (Meridia) Contraindications
• In addition, sibutramine should not be used by
patients who have:
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uncontrolled hypertension
coronary heart disease
congestive heart failure
Arrhythmias
stroke
severe renal or liver dysfunction
• Sibutramine should be used with caution in patients
with narrow-angle glaucoma.
Sibutramine
Sibutramine Trial of Obesity Reduction and
Maintenance (STORM)
• Half of the patients who began therapy achieved a 10%
weight loss
• More than a third of these patients maintained that
weight loss for 2 years.
• As expected, the subjects who were able to maintain
weight loss experienced predictable improvement in
metabolic risk factors.
Sibutramine – Side Effects
• Can result in dry mouth, constipation, headache,
insomnia, increased blood pressure, tachycardia.
• Should monitor all patients once a month for
hypertension and side effects
• Should take in the morning to avoid insomnia
Orlistat (Xenical)
• Pancreatic lipase inhibitor that blocks the absorption of
up to one third of ingested fat.
• In addition to helping reduce weight, orlistat has been
shown to also:
– lower plasma low-density lipoprotein cholesterol (LDL)
cholesterol levels.
– The decline in LDL cholesterol is greater than that expected due
to weight loss alone.
– Lower HgbA1C in diabetic patients
Orlistat Video
Orlistat (Xenical) Indications
Among obese patients who meet the criteria for antiobesity drug therapy, orlistat is most likely to benefit
those who:
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Do not feel hungry
Are not preoccupied with food
Eat out or order-in often
Have increased cardiovascular disease risk or multiple
cardiovascular risk factors
– Are older
– Take multiple medications
Orlistat is taken 3 times daily with meals
Orlistat
Effect of orlistat on dietary cholesterol absorption
• 18 obese (average BMI, 37 kg/m2) subjects with and
without orlistat therapy.
• Radiolabeled cholesterol tracer was given as part of a meal
Orlistat treatment was associated with a reduction in
cholesterol absorption from 53% to 40%, representing a
25% reduction in cholesterol absorption (P < .05).
B. Mittendorfer, et al.
Orlistat
Figure 3. A: Data from volunteers randomized to Int + P. B: Data from volunteers
randomized to Int + O. Baseline for plasma FFA ( ) and during a 4-h insulin infusion
and are plotted with corresponding values at 6 months ( ). There were significant
postintervention changes in plasma FFA in both groups. The changes were greater
with Int + O. *P < 0.05; †P < 0.01.
[Diabetes Care 27(1):33-40, 2004. © 2004 American Diabetes Association, Inc.]
Orlistat
EGP = endogenous glucose production and Rd = glucose utilization
[Diabetes Care 27(1):33-40, 2004. © 2004 American Diabetes Association, Inc.]
Orlistat
• 6 obese (BMI, 38 kg/m2), insulin-resistant males treated
with orlistat for 3 months.
• All subjects were instructed to maintain their weight at a
constant level.
• Using a euglycemic-hyperinsulinemic clamp technique,
these investigators measured insulin sensitivity before
starting orlistat, after 3 months of therapy, and at 3
months after stopping therapy.
• Insulin sensitivity increased by 42% after 3 months of
orlistat treatment despite no change in weight.
• Insulin sensitivity declined to baseline again after
stopping orlistat treatment.
D. B. Dahl et al.
Orlistat- Effect on HgbA1C in T2DM
The improvement
in HbA1c achieved with
orlistat therapy
exceeded that of the
placebo group and there
was a 0.62% improvement
in HbA1c relative to the
baseline value for the
participants randomized to
orlistat.
Figure 4—HbA1c over 1 year of double-blind treatment with placebo (E) or 120 mg orlistat (F).
P0.002, least-squares mean difference from placebo in the change from baseline over 52 weeks.
DIABETES CARE, VOLUME 25, NUMBER 6, JUNE 2002
Orlistat- XENDOS
• 4-year, double-blind, prospective study
• 3,305 patients we randomized to lifestyle changes
plus either orlistat 120 mg or placebo, three times
daily.
• Participants had a BMI 30 kg/m2 and normal (79%)
or impaired (21%) glucose tolerance (IGT).
• Primary endpoints were time to onset of type 2
diabetes and change in body weight.
Orlistat- XENDOS
Orlistat- XENDOS
• After 4 years’ treatment, the cumulative
incidence of diabetes was:
– 9.0% with placebo
– 6.2% with orlistat
• This corresponds to a risk reduction of 37.3%
in all patients (P 0.0032).
• Risk reduction in patients with IGT was 45.0%
Orlistat- XENDOS
Orlistat – Side effects
• Because it blocks intestinal absorption of fat it can result
in diarrhea and steatorrhea
• This is minimized by maintaining a strict low fat diet
(<30% of diet)
• Another concern is the loss of fat soluble vitamins with a
potential for malnutrition.
• To prevent this, recommend a daily multivitamin for all
patients on this therapy
Investigational Agents for
Treatment of Obesity
Topiramate
• Topiramate is a novel antiepileptic drug approved by the
FDA as an antiseizure medication.
• When reports surfaced that patients enrolled in initial
trials of the drug and also in clinical practice were
experiencing unexpected weight loss, the effects of the
drug on weight began to be studied.
• Mechanism for weight loss is still poorly understood
Topiramate
• 34 patients being treated for epilepsy.
• 12-month open-label trial without dietary intervention,
patients took combinations of drugs to treat their
epilepsy.
Dr. Ulf Smith, Sahlgrenska University Hospital, Göteborg, Sweden
Topiramate
• Results:
– Body weight for the group as a whole declined from 77.5 kg to
71.6 kg (P </= .01).
– Weight loss was most pronounced in obese subjects, whose
average body weight dropped from 96.5 kg to 85.5 kg at 12
months.
– The weight loss was almost completely in fat mass rather than in
lean body mass.
– In the group that lost more than 10% of their body weight, the fatmass reduction averaged 28%.
• Although some reduction in caloric intake was noted,
energy expenditure studies were not performed.
Dr. Ulf Smith, Sahlgrenska University Hospital, Göteborg, Sweden
Topiramate
• Another study: Effects of topiramate on body fat after
a low-calorie diet induced weight loss.
• Obese subjects (BMI >/= 30 and </= 50 kg/m2) who
lost 8% of their weight after 8 weeks of 800-1000
kcal/day diet were randomized to receive placebo,
96 mg topiramate daily, or 192 mg topiramate daily.
Topiramate
• After 32 weeks, the changes in body weight were:
– Placebo
– 96-mg
– 192-mg
-11.2%,
-16.3% (P </= .001)
-17.3% (P </= .001)
• Visceral abdominal fat (VAF) measured by MRI after
32 wks:
– Placebo
– 96-mg
– 192-mg
-27.1%,
-36.7% (P </= .001)
-34.7% (P </= .001)
Leptin
•Naturally occurring hormone that plays a role in satiety
and weight maintenance.
•Produced in adipocytes
•Its role in weight regulation is related to its effects on the
hypothalamus, where it leads to:
• satiety
•decreased food intake
•increased energy expenditure in the periphery
Leptin
• Initial human trials with recombinant leptin were modestly
successful.
• Most subjects in the initial trial developed local reactions
at the injection site.
• Weight loss was relatively modest.
• However, the hormone needs to be given
subcutaneously and has a short half-life.
• Thus a modified recombinant human leptin (m-leptin)
was created that has a longer half-life.
Leptin
• 270 obese (average BMI, 33 kg/m2) volunteers
were recruited and advised to begin a 500 kcal/d
dietary deficit.
• Subjects were divided into 3 groups:
– Group 1 received either 20 mg/d of m-leptin or placebo.
– Group 2 received either 80 mg of m-leptin 3 times per week or
placebo,
– Group 3 received either 240 mg of m-leptin per week or placebo.
Dr. Ken Fujioka, Director of the Nutrition and Metabolic Research Center at Scripps Clinic, La Jolla, California.
Leptin
• Results:
– Group 1: strong placebo effect, both the m-leptin-treated and
placebo-treated subjects experiencing comparable weight loss.
– Groups treated with the higher doses of m-leptin had greater
weight loss
– Those who received m-leptin at any dose lost an average of 3%
of their body weight (6 or 7 lb) during 6 months.
• Some subjects, however, lost much more weight, but this
was mostly in the groups receiving the higher doses.
– Eleven percent of the m-leptin-treated patients in group 3 lost
10% or more of their body weight.
• The weight that was lost was almost completely fat.
Dr. Ken Fujioka, Director of the Nutrition and Metabolic Research Center at Scripps Clinic, La Jolla, California
Conclusion
Pharmacotherapy of Obesity
• Diet/lifestyle changes remain the mainstay of the treatment
of obesity
• In patients not reaching goals, drugs can be an important
tool
• Expect only modest weight loss at best with current drugs
• Be aware of Rx indications and contraindications
• Off label use of non-indicated products is not recommended
• Investigational agents may offer hope for treatment of
obesity in the future